A COMPARATIVE STUDY OF EFFICACY OF LETROZOLE
VERSUS CLOMIPHENE CITRATE IN OVULATION
INDUCTION IN PATIENTS WITH POLYCYSTIC OVARIAN
Dissertation submitted to
THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITYin partial fulfilment for the award of the Degree of
M.D. OBSTETRICS AND GYNAECOLOGY
INSTITUTE OF OBSTETRICS AND GYNAECOLOGY
MADRAS MEDICAL COLLEGE
CHENNAI – 600 003.
This is to certify that the dissertation titled COMPARATIVE STUDY OF EFFICACY OF LETROZOLE VERSUS CLOMIPHENE CITRATE IN OVULATION INDUCTION
submitted by Dr. G. THIRIPURASUNDARI to the faculty of Obstetrics and Gynaecology, The Tamilnadu Dr. M.G.R. Medical University, Chennai in partial fulfillment of the requirement for the award of M.D. Degree (Obstetrics and Gynaecology) is a bonafide research work carried out by her under our direct supervision and guidance.
Dr. J. MOHANASUNDARAM
M.D. D.N.B., Ph.D.,
Madras Medical College, Chennai – 600 003.
Dr. REVATHY JANAKIRAM
M.D. D.G.O., M.N.A.M.S.
Institute of Obstetrics and Gynaecology Madras Medical College,
I hereby declare that the study entitled COMPARATIVE STUDY OF EFFICACY OF
LETROZOLE VERSUS CLOMIPHENE CITRATE IN OVULATION INDUCTION was
done by me in the Institute of Obstetrics and Gynaecology (IOG), Madras Medical College, Chennai – 600 003, during the period of my PG study for MD Branch II Obstetrics and Gynaecology from 2007-2010.
This Dissertation to Dr. M.G.R. Medical University is in partial fulfillment of university regulations for the award of MD Degree in Obstetrics and Gynaecology.
Place : Date :
M.D. P.G. (Obstetrics and Gynaecology) Institute of Obstetrics and Gynaecology
I am extremely thankful to Dr.J.MOHANASUNDARAM, M.D., D.N.B., Ph.D., Dean,
Madras Medical College and Government General Hospital, Chennai and
Dr.K.SARASWATHI, M.D., D.G.O., Former Director and Superintendent, Institute of Obstetrics and Gynaecology, Egmore for granting me permission to utilize the facilities of the institute for my study.
I am immensely grateful to our Director and Superintendent Prof.Dr.REVATHI JANAKIRAMAN, M.D., D.G.O., M.N.A.M.S. Institute of Obstetrics and Gynaecology, Egmore,
Chennai for her concern and support in conducting this study.
I am extremely thankful to our Deputy Superintendent, Prof.Dr.SHANTHI DINAKARAN, M.D., D.G.O.,for her support in conducting this study.
I wish to express my deep sense of gratitude to Prof. Dr.G.LATHA, M.D., D.G.O., for
her valuable guidance and supervision through out my study.
I sincerely thank Prof. Dr.ANURADHA, M.D., D.G.O., for her great support and guidance in carrying out the study.
I am extremely thankful to all my Professors, Assistant Professors, Medical and Paramedical staffs of Institute of Obstetrics and Gynaecology, Chennai for their co-operation in conducting the study.
I am thankful to my mother and father and my brother Dr.G.MUTHUKUMARAN,
B.D.S., for their moral support throughout the study I thank all my patients for their kind
NO. TITLE PAGE NO.
2 PHYSIOLOGICAL BASIS OF OVULATION 1 3 DIAGNOSIS OF OVULATION 5
4 OVARIAN DYSFUNCTION 8
5 POLYCYSTIC OVARIAN SYNDROME (PCOS) 10 6 OVULATION INDUCTION 13 7 PHARMACOLOGY OF DRUGS 15 8 REVIEW OF LITERATURE 31
9 AIM OF STUDY 34
10 MATERIALS AND METHODS 35 11 RESULTS AND ANALYSIS 42
12 DISCUSSION 51
13 SUMMARY 54
14 CONCLUSION 55
15 BIBLIOGRAPHY 16 PROFORMA 17 MASTER CHART 18 ABBREVIATIONS
PHYSIOLOGICAL BASIS OF OVULATION
The Ovarian cortex at puberty contains hundreds of thousands of primordial follicles (1). Initially independent of gonadotropins, a cohort (hundreds) of primordial follicles is recruited to grow (2). During the early follicle development, the oocyte enlarge and the granulosa cells proliferate to form a preantral follicle. Over 3 – 6 months, the follicle develops FSH receptors in the granulosa cells and LH receptors in the theca cells (1). At this stage, antral follicles become acutely dependent on FSH for further development (1). Just before menses, falling estrogen levels result in with drawal of negative feed back centrally leading to increased gonadotropin levels (3). FSH stimulates granulosacell proliferation and differentiation, with the development of more FSH receptors and the production of aromatase (4). LH stimulates androstenedione production by theca cells that diffuses in to the granulosa cell providing substrate for estrogen secretion. This step is catalysed by the aromatase enzyme, which is induced by FSH. The so called two – cell, two – gonadotropin theory (5,6) postulated that FSH concentrations must exceed a certain level (FSH) threshold) before follicular development will proceed.
in larger antral follicles above 1 cm in diameter (9). Rapidly increasing levels of estradiol produced by the mature preovulatory follicle precede the mid cycle LH and FSH surge that will initiate ovulation. The circulating level of estradiol determines the time of LH surge. The alteration in steroidogenic pathway results in progesterone as the primary steroid hormone produced after leutinization (10). The corpus luteum retains the ability to produce estrogen. The demonstration of multiple follicular growth (11) suggests that some estrogen in the luteal phase is contributed by growing follicles that will under go atresia (12).
The corpus luteum undergoes regression with a fall in progesterone and estrogen and the onset of menses. FSH levels rise with withdrawal of estrogen negative feed back and the next cohort of follicles begins to develop.
In summary, normal follicular development culminates in ovulation of a nature oocyte, followed by the development of a corpus luteum producing adequate amount of progesterone. This sequence of events is orchestrated by the interaction of local ovarian factors and endocrine factors from the pituitary and hypothalamus. The presence of subtle abnormalities despite the occurrence of ovulation may be responsible for unexplained infertility.
FUNDAMENTAL TENET OF FOLLICULAR DEVELOPMENT TWO CELL TWO GONADOTROPIN THEORY (13,14,15)
Granulosa Cell FSH CAMP Circulation
Anovulation occurs occasionally in all women. It is probably not uncommon during the first 2 or 3 yrs of menstrual life and after the age of 40 yrs, the incidence may rise to as high as 1 in 5 cycles. In the active reproductive period, however not more than 1 in 50 regular cycles are anovular. For practical purpose, in mature women regular menstruation means regular ovulation.
DIAGNOSIS OF OVULATION
Analysis of symptoms
I. Cyclical Bleeding: Regular normal menstrual loss is strong presumptive evidence of monthly ovulation.
II. Ovulation pain (Mittleschmerz): Some discomfort in the hypogastrium or in one or other iliac fossa for 12 – 24 hrs just before or just after ovulation.
III. Ovulation Bleeding or discharge (Mittelblut) : Slight loss of blood or of mucus tinged with blood at the time of ovulation, sometimes associated with ovulation pain.
IV. Premenstrual Mastalgia: Premenstrual pain and tenderness in the breasts is related to corpusluteum action.
VI. Changes in Endometrium: The evidence that ovulation has occurred predicted by secretory activity in the gland during the week preceding or at the onset of menstruation by endometrial biopsy. But is not accurate.
VII. Change in cervical Mucus: At the time of ovulation mucus is thin and profuse with great elasticity and with stand stretching up to 10cm – spinn barkeit or thread test.
Vaginal Smear cytology
Cells Superficial Cells
Estrogenic Phase 0 20 80 Progesteronic Phase 0 80 20
Hormonal levels in different phases of Menstrual cycle
Hormone F.P Ovulation L.P Menstrual
FSH 5 – 15 m IU/ml 12 – 30 2 – 9 3 – 15 LH 6 – 14 m IU/ml 25 – 100 2 – 13 3 – 12 E2 100 – 200 pg/ml 300 – 500 100 – 200
P 1 ng/ml - 15 ng/ml
Helpful in the induction and confirmation of ovulation. The graffian follicle grows at the rate of 1 -2 mm/day. Attains the size of 20 mm or more at ovulation
• Sudden shrinkage in size of a follicle
• Appearance of free fluid in POD
• Regrowth of the collapsed cyst
According to WHO (1976) classification
Group I Hypothalamic pituitary failure
- Anorexia nervosa
- Kallmann’s syndrome
- Sheehan’s syndrome
Group II Hypothalamic pituitary dysfunction
- Adrenal tumours
- Androgen producing ovarian tumours
Group III Ovarian failure - Turner syndrome
- Pure gonadal dysgenesis
- Swyer syndrome
Group IV Congenital or Acquired genital tract disorders (Eg) Imperforate hymen, MRKH syndrome, Asherman’s syndrome.
Group V Hyperprolactinemia with SOL (Eg) pituitary adenoma.
Group VI Hyperprolactinemia without SOL (Eg) Hypothyroidism, CRF, drug induced.
POLYCYSTIC OVARIAN SYNDROME (PCOS)
It is a complex disorder with heterogeneous clinical and endocrine factors. Incidence in the reproductive age group is around 20 – 22% (Polson et al 1988) (16). Polycystic ovaries have its origin during adolescence and is thought to be associated with increased weight gain during puberty (Belen and Danger 1995) (17).
Clinical features :
PCOS PCOD (poly cystic appearing ovaries) Asymptomatic 20%
Obesity 40% High BMI
Upper body obesity Infertility 20 – 50% Ovulatory dysfunction Abnormal folliculogenesls Hyperandrogenism 66%
Acne, hirutism, Alopecia, Seborrhea.
Menstrual Irregularity 70% Oligomenorrhea Amenorrhea Intermenstrual
CRITERIA (1) The NICHD (1990)
(2) The ESHRE & ASRM / Rotterdam (2003)
(3) AES criteria (2006)
Rotterdam Criteria (1) Oligo / chronic anovulation
(2) Clinical / Biochemical Evidence of
(3) USG E/o polycystic ovaries exclude other causes of hyperandrogenism
Biochemical / Endocrine Abnormalities
1. Raised LH
2. Raised LH: FSH ratio
3. Raised Androgen – Testosterone and androstenedione
4. Raised circulating estrogen
5. Raised fasting Insulin
6. Raised fasting glucose
7. Raised prolactin
8. Decrease in SHBG
9. Raised testosterone : SHBG ratio
1. Dysliplidemia - TGL > 140 mg/dl
HDL < 40 mg/dl
2. Insulin resistance, fasting plasma Insulin > 110 mg/dl
3. Obesity BMI > 25 kg /m2 or
WHR > 0.85 or waist > 100 cm
4. BP > 140 / 90 mm Mg
Ovulation Induction refers to the therapeutic restoration of the release of one egg per cycle in the woman who either has not been ovulating regularly or has not been ovulating at all. Although it is usually acceptable for OI to result in the release of two eggs, one should avoid the ovulation of more than two eggs in an effort to minimize the risk of OHSS and multiple gestation.
Appropriate patient selection can be a significant determinant of the success of OI among PCOS patients.
Once ovulation has been documented for a particular treatment. Patients should be mentally prepared to continue with that regimen for at least 3 cycles. Because for most treatment the rate of a pregnancy occurring per therapeutic cycle is the same for each of the first three cycles.
It is mandatory to exclude male factor infertility by means of semen analysis and bilateral tubal patency by HSG.
OVULATION INDUCTION DRUGS
1. SERMS - Clomiphene citrate
(1) Insulin sensitizers
Menotropins (2) Gonadotrophins
recombinant Gonadotropins pulsatile Gn RH
(3) Gn RH
with HMG alone Gn RH agonist
with FSH / HMG (4) Dopamine Agonists
PHARMACOLOGY OF DRUGS
For more than 40 yrs, CC has been the most commonly used oral agent for OI. In 1961, Greenblatt et al., (19), published the first results of OI achieved by CC (at that time known as MRL / 41). But CC is considered pregnancy risk category X. CC belong to the category of SERMs.
1. Designer estrogens with combined effects of estrogen antagonism and partial agonism.
2. Nonsteroidal analogues with tissue specific activity
3. Differential modulation of estrogen receptors results in multiple target system.
1. I generation Triphenyethylene compounds :
- Tamoxifen - Toremifene - Droloxifene - Idoxifene - Clomifene
5. Benzopyrans - Ormeloxifene
- Breast ca – adjuvant - Prevention of osteoporosis - Cardio protective agent
CC is an orally administered nonsteroidal ovulatory stimulant designated chemically as
Molecular formula : 2 –(4 –(2 – Chloro -1, 2- diphenyl ethinyl phenoxy) – N – N – diethyl Ethan amine
C28 H28 C1NO . C8 H8 O7 Molecular weight - 598.10
C2H5N CH2 CH2O C6H8O7
Isomers : CC is a diastereomeric mixture of two geometric isomers
30% Zuclomiphene (cis isomers, formerly called Transclomiphene) (Emst et al., 1976).
62% enclomiphene (Trans isomer – formerly called is clomiphene) (Holtkamp et al., 1987).
Zuclomiphene is mildly estrogenic as well as antiestrogenic.
Enclomiphene is entirely antiestrogenic.
Mechanism of Action
- CC acts as competitive antagonist of 17B Estradiol at the level of cytoplasmic nuclear receptor complex.
- Blockade of estrogen receptors in the hypothalamic arcuate nucleus leads to an increase in Gn RH.
- Increases the pituitary sensitivity to Gn RH (23).
- Increases pulse amplitude but not frequency in anovulatory women with PCOS, in whom the Gn RH pulse frequency is already abnormally high (24).
- FSH and LH secretion is increased (Dickey et al., 1965) (25).
- Hence serum progesterone and estradiol concentration rises during luteal phase in a direct dose response relation ship (Hammond et al., 1982 ; Fukuma et al., 1983). Supraphysiological levels of estrogen can occur without central suppression of FSH because the normal ER-mediated feed back mechanisms are blocked as a result of prolonged ER depletion (22). As a result the FSH window being extended – leading to multiple follicle growth and a higher multiple pregnancy rate with CC.
Anti estrogenic effects of CC
CC is excreted principally through intestine 5 days after oral administration 51% has been excreted. However some CC continues to be excreted for at least 6 wks (Mikkelson et al., 1986).
- Peak plasma concentrations of zuclomiphene occurs 6 hrs after oral administration of 50 mg.
- A steady state 25% reached at 48 hrs remains constant for the next 14 days.
- Single dose studies showed that Zuclomiphene (cis) has a longer half life than enclomiphene (trans). Detectable level persisted for longer than a month.
INDICATION AND DOSAGE
1. Anovulatory Infertility; PCOS 2. Unexplained Infertility
3. Amenorrhea – Galactorrhea syndrome 4. Psychogenic amenorrhea
5. Post oral contraceptive amenorrhea
6. Certain cases of secondary amenorrhea of undetermined etiology.
cyst. Therapy is begun with in the first 5 days after the onset of a spontaneous or progesterone induced menses and continued for 5 days (D3 – D7 of cycle) (31). US FDA recommends maximum dosage of 100 mg /day. Considerable clinical experience with CC indicates that a dosage up to 250 mg/d is safe (32).
If ovulation does not occur after 3 cycles of therapy, further treatment with CC is not recommended and the patient should be re evaluated.
ADVERSE EFFECTS %
Ovarian enlargement 13.6%
Vasomotor flushes 10.4%
Abdominal pain / discomfort 5.5%
Distension / Bloating
Nausea / vomiting 2.2%
Breast discomfort 2.1%
Visual symptoms 1.5%
(Blurred vision, lights, floaters, waves, photophobia, diplopic, scotomata)
The most serious Complication of CC therapy-OHSS(ovarian Hyperstimulation syndrome)
3. AUB of undetermined origin
4. Ovarian cyst
5. Uncontrolled adrenal or thyroid dysfunction or presence of intracranial lesion such as pituitary tumors.
CLOMIPHENE SET BACKS
• Discrepancy between ovulatory and pregnancy rates
• Poor endometrium 30% (peripheral anti estrogenic effect)
• Thickness < 6 mm
• Decreased glandular density
• Decreased uterine blood flow
• Extended FSH window – Multifollicular ovulation
A large number of AIs have been developed over the last 30 yrs with the most recent, III generation AIs.
Aromatase is a microsomal cytochrome P450 hemoprotein containing enzyme (the product of CYP 19 gene) and catalyses the rate limiting step in the production of estrogen. Aromatase activity is also present in ovaries, brain, and adipose tissue, muscle, liver, breast tissue (33,34).
AROMATASE CONVERTS TESTOSTERONE TO ESTRADIOL
Generation Non steroidal Steroidal I Aminoglutethimide
II Rogletimide, Fadrozole Formestane III Anastrazole, Letrozole, Exemestane
Vorozole (suicide inhibitor)
Non selective - Aminoglutethimide, Testolactone (Teslac) Selective - Anastrazole Zn 1033 (Arimidex)
Letrozole Gn 20267 (Femara) Exemestane (Aromasin)
Vorozole (Rivizor) Formestane (Lentaron) Fadrozole (Afema)
It is a third generation AI. Highly selective and highly potent inhibitor of Aromatase in vitro, in vivo in animals and in humans.
MOLECULAR STRUCTURE (35) :
4-4'-(1H-1, 2, 4 - Triazol - 1 - yl methylene) diabenzonitrite ;
4-(C4 - cyanophenyl) - (1,2,4 - Triazol - 1 - yl methyl)
MECHANISM OF ACTION
- Block estrogen negative feed back, without depletion of ER.
- Both circulating estrogen and locally produced estrogen in the brain exert negative feed back on gonadotropin release (38 – 41).
- Inhibition of aromatization Block E production from all sources
Release HP axis from estrogenic negative feed back increase in Gonadotropin secretion growth of follicles (Casper and Mitwally) (42).
AI do not antagonize the ERs in the brain and the initiation of follicle growth accompanied by increasing concentrations of both estradiol and inhibin results in a normal negative feed back loop that limits FSH response, thereby avoiding the risk of high multiple ovulation and OHSS.
PERIPHERAL MECHANISM OF ACTION
- Increased follicular sensitivity to FSH.
- Temporary accumulation of intraovarian androgen – amplifies FSH effects – stimulates IGF–1 synergize with FSH to promote folliculogenesis (43-46).
CHANGES IN THE ENDOMETRIUM
- Upregulation of ERs in the endometrium leading to rapid endometrial growth.
- Used alone for OI in WHO group II dysfunction.
- As an adjuvant in conjunction with exogenous FSH or other medications to improve the out come of OI.
- Induction of ovulation in CC failures (47).
- Along with FSH for super ovulation for IUI or IVF (50% reduction in dose of FSH required) (48).
- Optimal dosage 2.5 – 5 mg from D3 – D7
- Single dose 10 – 30 mg on D3 shows similar rates of ovarian stimulation.
- Single high dose 60 mg has been reported without any negative effects.
- Letrozole is rapidly and completely absorbed (99.9% bioavailability).
- Extensively distributed to tissues.
- T½ of Letrozole – 42 hrs.
- Area under cure (AUC) is greater in patients with breast cancer due to reduced metabolic clearance. Metabolized to a pharmacologically inactive carbinol metabolite (4,4’ – methanol bis benzo – nitrite) and excreted by kidneys. Of the radiolabel recovered in urine, 75% was the glucoronide of carbinol metabolite, 9% - 2 unidentified metabolites & 6% - unchanged letrozole.
In human liver microsomes letrozole strongly inhibited CYP2 A6 and moderately inhibited CYP2c 19.
I gen II gen IIIgen Aminoglutethimide 4 – OHA
Co-administration of Letrozole and Tamoxifen 20 mg resulted in reduction of plasma levels of letrozole by 38% (36).
sweating at night.
Moderate decrease in lymphocyte counts
Allergic reaction – rare.
Less common - Constipation
Embryologic and fetotoxic as indicated by
Decreased number of live fetuses
Total anomalies including absence and
Shortening of renal papilla,
Dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals
Mono follicular ovulation & decreased multiple pregnancy, OHSS & less monitoring
Convenience of administration & low cost
Reduction in amount of FSH used for superovulation
REVIEW OF LITERATURE
V ATAY, C CAM, M MUHCU et al 2006 compared Letrozole with CC as a first line treatment for OI in with PCOS. Randomized a total of 106 women with primary infertility. Concluded that Letrozole is associated with better ovulation induction 16.5% and higher pregnancy rate and as a first line treatment for anovulatory patients with PCOS.
A BILJAN AND COLLEAGUES (74) conducted prospective, randomized, controlled trial of CC Vs Letrozole for OI in women with unexplained infertility & concluded that Letrozole was an effective alternative to CC in view of monoovulation, endometrial thickness and blood flow. The pregnancy rate was 5.6% in the CC group and 10.7% in the Letrozole group.
BASIR et al (10) conducted a comparison study of Letrozole with CC in women with unexplained infertility and concluded that Letrozole is effective as a first line treatment for OI.
VENDOLA et al 1998 studied the use of Letrozole in OI with anovulatory infertility and concluded that high risk of ovarian hyperstimulation syndrome and multiple ovulation was less compared with CC.
GOSWARNI et al., 2004; SCHOOL CRAFT et al, 2004 ; VERPOEST et al., 2006
conducted clinical studies of AIs for ovarian stimulation in IVF and have shown that AIs could be a low – cost alternative to natural cycle IVF in patients who are poor responders to FSH
for OI. Ovulation occured in 75% of patients and pregnancy was achieved in 25%
ELNASHAR et al., 2006 conducted studies of use of AIs for OI and concluded that Letrozole had an ovulation rate 54.6% and pregnancy rate 25% higher than CC.
ATAY et al, 2006 assessed the efficacy of AIs for OI compared with CC. 106 women with oligomenorrhea and PCOS were enrolled. Results were more favourable in the Letrozole group than in CC group regarding the percentage of ovulatory cycles (82.4% Vs 63.6%), pregnancy (21.6% Vs9.1%), monofollicular cycles (1.2 Vs 2.4 follicles > 18 mm on the day of hcG administration) and endometrial thickness (8.4 mm Vs 5.2 mm).
BAYER et al 2006, 36 patients (95 cycles) were given CC and 38 patients (95 cycles) given Letrozole concluded that Letrozole is better than CC in terms of ovulation rate (74.5% Vs 65.7%) or pregnancy rates (7.4% Vs 9%)
SOHRABVAND et al 2006 conducted studies on PCOS women resistant to CC and concluded that endometrial thickness was higher with Letrozole than CC.
AIM OF STUDY
MATERIALS AND METHODS
A prospective, randomized, parallel, multicentric comparative trial
PERIOD OF STUDY
2008 – 2009
PLACE OF STUDY
Department of fertility research clinic, IOG, Egmore
SELECTION OF CASES
100 women belonging to eligible criteria of age (21 – 35 yrs) after obtaining informed consent from each participant.
ARMS ASSIGNED INTERVENTIONS
1. Experimental Drug: Letrozole 2.5 mg OD
for 5 days (D3 – D7)
2. Active Drug: CC 50 mg OD
Comparator for 5 days (D3 – D7)
1. Age : 21 – 35 yrs
2. Period of Infertility
3. PCOS with at least 2 of Diagnostic criteria
Oligomenorrhea / Amenorrhea
Clinical evidence of Acne / hirsutism
USG evidence of PCOS
4. Normal semen analysis
5. Normal pelvic USG
6. Normal bilateral tubal patency
7. No recent treatment for OI (with in 6 months)
8. Willingness and giving written informed consent
1. Women with uterine /adnexal pathology (Eg) fibroid, ovarian cyst are excluded from the study.
2. Women with clinical features of hyperthyroidism, hypothyroidism are excluded.
4. Those with impaired hepatic / renal function were excluded
5. Women with RBS> 140 mg/d/ were excluded from the study
6. Age > 35 yrs and obese patients were excluded from this study
7. Lack of willingness.
The participants in this study were subjected to history, clinical and biochemical evaluation.
Age (21 – 35 yrs) : An association between age of the woman and reduced fertility has been well documented (65). The decline in fecundability begins in early 30s and accelerates during late 30s and early 40s. Oocyte related decline in fertility is due to decreased ovarian reserve (66).
Period of Infertility : Failure to conceive during 12 – 18 mth despite unprotected regular coitus justifies full investigations. When the women age > 30 yrs and man > 40 yrs – investigations should not be delayed.
oligomenorrhea, amenorrhea & menorrhagia. In our study women with oligomenorrhea were subjected to the study after progesterone withdrawal bleed. Women with primary amenorrhea were excluded from our study.
History related to previous surgeries related to genital tract, H/o appendicitis, peritonitis and H/o genital tract TB were excluded from this study.
The patients enrolled in our study were subjected to clinical examination which included.
1. All patients height and weight was measured. BMI was then calculated.
BMI = wt in kg. / Ht in m2 It is a reliable indicator, Inexpensive and easy to perform.
Measurement units Formula & Calculations Kg & m (or cm) wt (kg) / (Ht (m) )2
Ht in cm by 100 = Ht in m pounds & inches wt (Ib) x (Ht (inches))2 x 703
conversation factor - 703 Interpretation
< 18.5 Under weight 18.5 – 24.9 Normal 25.0 – 29.9 Over weight 30.0 – 39.9 Obese
40.0 & More Extreme obesity
2. All patients waist (in cm) and WHR measured
Significance : Upper body obesity (male type) with a WHR > 0.9 associated with higher risk of long term morbidity (Pasquali et al., 1994).
3. Clinical evidence of acne, hirsutism, acanthosis nigricans, hyper thyroidism and hypothyroidism were looked for in all patients enrolled in our study.
Significance : Hirsutism and acne are the commonest manifestation and are associated with menstrual irregularities and obesity. Usually degree of hirsutism is quantified by Ferriman– Gallway scoring system. Score begins from o (no excusive terminal hair growth) to 4 (extensive terminal hair growth) & the numbers added up to maximum of 36.
USG evidence of PCOS : All patients had antral follicle count of at least 10 with size 2 – 9 mm. The ovarian volume = / > 10 ml. Evidence of fibroid & ovarian cyst / adnexal masses ruled out.
5. Semen Analysis WHO (2002) Normal Analysis:
Sperm concentration > 20 million / ml
Sperm motility > 50% progressive or 25% rapidly
Morphology > 15% normal form
White blood cells > 1 million / ml
Immuno bead or mixed anti globulin reaction test < 10% coated.
III. Biochemical Investigations
1. Complete blood count, random blood sugar, renal function test and liver function test done in all patients. Any abnormality in any one of these investigations, those patients were excluded from this study.
RESULTS AND ANALYSIS
The selected randomized patients were allocated as Group L and Group CC, of which Group L patients were administered Letrozole 2.5 mg OD from D3-D7 of the menstrual cycle and Group CC patients were administered CC 50 mg OD from D3-D7 of the menstrual cycle. Both the group of patients, was subjected to transvaginal ultrasonographic monitoring of number of follicles, Maximum diameter of the largest follicle, and endometrial thickness from D11 onwards. The serum progesterone levels were measured on Day 21 which indicates the definite occurrence of ovulation. The treatment was discontinued in both the groups, if patients, developed ovarian enlargement.
The number of follicles, mean diameter of the largest follicle, ovulation rate, endometrial thickness and serum progesterone values were compared in the two groups. A group test or the students test was used to compare data as appropriate. A value < 0.05 was considered to be statistically significant.
TABLE - 1
AGE GROUP - CROSS TABULATION
L CC Total
Yrs. Count % within Group 72.0%72 71.0%71 71.5%143 26-30
Yrs. Count % within Group 20.0%20 18.0%18 19.0%38 31-35
% within Group
8 8.0% 11 11.0% 19 9.5% Total Count % within Group 100.0%100 100.0%100 100.0%200
Value df Asymp. Sig. (2-sided)
Pearson Chi-square 0.586a 2 0.746 Likelihood Ratio 0.588 2 0.745 Linear-by-Linear
0.187 1 0.665
N of Valid Cases 200
a 0 cells (.0%) have expected count less than 5. The minimum expected count is 9.50.
Age Group N Mean Std.
Std. Error Mean
L 100 24.8800 3.18862 0.31886 CC 100 25.1600 3.32338 0.33234
TABLE - 2
MEAN DURATION OF INFERTILITY
Independent Samples Test
Infertility Group N
Deviation p Value
L 100 2.4400 0.60836
CC 100 2.4300 0.59041 0.906
The mean duration of infertility in Group L is 2.44 years and in Group CC is 2.43 years with p value is 0.906 (> 0.05). Not significant Both the groups are comparable with respect to mean duration of infertility.
TABLE - 3
BMI Group N DeviationStd. p Value
L 100 22.5300 3.13831
CC 100 22.6880 3.74226 0.747
The mean body mass Index in Group L is 22.53 with S.D. of 3.138. The mean body mass Index in Group CC is 22.68 with S.D. of 3.742.
TABLE - 4
Ratio Group N
Deviation p Value
L 100 0.8276 0.2675
CC 100 0.8273 0.2831 0.939
The mean WHR in Group L is 0.8276 with S.D. of 0.267 Group CC is 0.827 with S.D. of 0.283.
Both the groups are comparable with respect to WHR with p value 0.939 (>0.05) Not Significant.
TABLE - 5
L CC Total
% within Group
83 83.0% 78 78.0% 161 80.5% Hirsutism Count % within Group 17.0%17 22.0%22 19.5%39
L CC Total
No Oligo Menorrhea
% within Group
74 74.0% 73 73.0% 147 73.5% Oligo
Menorrhea Count % within Group 26.0%26 27.0%27 26.5%53 Total Count % within Group 100.0%100 100.0%100 100.0%200
L CC Total
Count % within Group
83 83.0% 77 77.0% 160 80.0% Amenorrhea % within GroupCount 17.0%17 23.0%23 20.0%40
Total % within GroupCount 100.0%100 100.0%100 100.0%200
17% of the cases in Group L had clinical evidence of hirsutism. 22% of the cases in Group CC had hirsutism.
26% of the cases in Group L and 27% of the cases in Group CC had oligomenorrhea.
17% of the cases in Group L and 23% of the cases in Group CC has history of amenorrhea.
After excluding pregnancy by urine gravindex method, these patients were subjected to the study after progesterone withdrawal bleed.
L CC Total
Not Ovulated Count % within Group 33.0 %33 48.0%48 40.5%81
Ovulated Count % within Group 67.0 %67 52.0 %52 59.5 %119
Total Count % within Group 100.0%100 100.0%100 100.0%200
CHI-SQUARE TESTS df Asymp. Sig. (2 sided) Exact Sig. (2-sided) Exact Sig. (1-sided)
Pearson Chi-square 9.778b 1 0.002 Continuity Correction 8.909 1 0.003 Likelihood Ratio 9.862 1 0.002
Fisher’s Exact Test 0.003 0.001 Linear-by-Linear
Association 9.729 1 0.002 N of Valid Cases 200
The ovulation response group tabulation shows that of 100 patients in L group, 67% ovulation occurred. 52% ovulation rate occurred in CC group. By applying chi-square tests, chi-square value 8.909 p value 0.003. (<0.05) = Significant. This shows that there is statistically significant difference in ovulation induction rate between the group of patients treated patients with L and CC. Letrozole treated patients had better ovulation rates than CC.
NUMBER OF FOLLICLES IN L & CC GROUP
Follicle Count % within Ovulation 33.0%33 48.0%48 40.5%81 One
% within Ovulation
52 77.6% 6 11.5% 58 29.0% Two
Follicles Count % within Ovulation 22.4%15 44.2%23 19.0%38 Three
Follicles Count % within Ovulation 0.0%0 44.2%23 11.5%23 Total Count
% within Ovulation
67 100.0% 52 100.0% 200 100.0% CHI-SQUARE TESTS
df Asymp. Sig.(2 sided)
Pearson Chi-square 100.000a 3 0.000 Likelihood Ratio 138.469 3 0.000 Linear-by-Linear
Association 84.366 1 0.000 N of Valid Cases 100
a. 2 cells (25.0%) have expected count less than 5. The minimum expected count is 2.88.
The cross tabulation shows that of 100 patients studied in Letrozole group, 52% of the cases developed single follicle, 15% of the cases developed two follicles. 33% of the cases did not ovulate with Letrozole.
= .000 (< 0.05) highly significant.
Letrozole treated cases had better monofollicular ovulation rates than CC treated group.
Follicle Group N
Deviation p Value
L 67 21.1560 2.40499
CC 52 18.7635 2.35614 < 0.05
The table shows the mean diameter of largest follicle in L group is 21.15 mm with a S.D. of 2.404. In CC group, the mean diameter is 18.76 mm with a S.D. of 2.356 p value of 0.000 (<0.05) obtained which is highly significant.
Thickness Group N DeviationStd. p Value
L 67 8.6090 0.43753 CC 52 7.1115 0.60929
In CC group the mean Endometrial thickness is 7.11 m with a S.D. of 0.609 P value obtained is 0.000 (<0.05) = High Significant.
TABLE – 10 GROUP STATISTICS
Group N DeviationStd. Error Std.
L 67 13.4164 1.57688 CC 52 12.2788 1.87191
0.000 (< 0.05)
A prospective randomized study was conducted in IOG during January 2008- Feb 2009. Of 200 patients who attended the infertility clinic 100 patients recruited in L group were allocated to receive 2.5 mg OD from D3-D7 of the menstrual cycle. 100 patients recruited in CC group were allocated to receive 50 mg OD from D3-D7 of the menstrual cycle. Both groups were comparable with respect of age, mean duration of infertility, BMI and WHR which had no statistically significant difference.
The patients recruited in both the groups were evaluated for evidence of acne, hirsutism, oligo / amenorrhea.
Our patients enrolled in both the groups were also evaluated for the presence of clinical evidence of hyperthyroidism and hypothyroidism.
In our study 17% of cases in L group and 22% of cases in CC group had hirsutism. 17% of cases in L group and 23% of cases in CC group had a history of amenorrhea. After excluding pregnancy for these patients by performing an urine gravindex method, these patients were included in our study after progesterone withdrawal bleed.
BADAWY et al., 2007 studied 438 infertile women with polycystic ovarian syndrome and concluded that ovulation rates was better in L group (84% Vs 60%) and endometrial thickness was better in L group than CC group (9.2 vs 8.1 mm).
In our study, the ovulation rate in L group was 67% and that of CC group 52%
VATAY, C CAM M MUHCU et al., in his study concluded that L is associated with better ovulation rate and can be used as first line treatment for anovulatory patients with polycystic ovarian syndrome.
In our study, 52% of the cases had monofollicular ovulation in L group where as in CC group only 6% of the cases developed single follicle and 23% of the cases developed two follicles.
BILJAN AND COLLEAGUES in his study concluded that Letrozole was an effective alternative to CC in view of monoovulation.
BASIR et al., in his study concluded that L is an effective alternative to CC for OI.
In our study, the mean endometrial thickness was better in Letrozole group than CC group (8.6 mm vs 7.1 mm).
The mean endometrial thickness (7.1 mm) in CC group indicates the adverse effects of CC on the endometrial growth that is thought to be due to depletion of the endometrial receptors.
with L group than CC Group.
In our study the mean diameter of largest follicle was greater in L group than CC group (21.15mm Vs 18.76 mm). The serum progesterone levels measured on D21 indicated the definite occurrence of ovulation was 13.41 ng/ml in L group and 12.27 ng/ml in CC group.
MITWALLY et al., in his study reported that use of letrozole is associated with significantly lower multiple pregnancy rates they explained this results by the fact that Letrozole induce limited number of mature follicles.
In a similar study, sh Tehrani Nejad, et al., (Journal of Assisted Reprod and Genet, 2008) demonstrated that Letrozole was a better alternative to cc-gonadotropin in patients with unexplained infertility (63).
In the patients recruited in this study,
1. The mean age in L group was 24.8 yrs and in CC group 25.1. years.
2. The mean duration of infertility in L group was 2.43 years and in CC group 2.44 years.
3. In Letrozole group, the ovulation rate was 67% and in CC group 52%.
4. In Letrozole group, 52% of the cases developed single dominant follicle and 15% of the cases had developed two dominant follicles.
5. In CC group only, 6% of the cases had monofollicular ovulation and 23% of the cases developed two follicles.
6. The mean diameter of largest follicle in L group is 21.15 mm and in CC group 18.76 mm.
7. The mean endometrial thickness is L group is 8.6 mm and in CC group 7.1 mm.
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OCCUPATION : SOCIO ECONOMIC STATUS : MARITAL STATUS : PERIOD OF INFERTILITY :
BODY MASS INDEX (kglm2 ) : WAIST (CM ) : WAIST HIP RATIO : SEMEN ANALYSIS : MENSTRUAL HISTORY : OLIGOMENORRHEA :
CLINICAL EVIDENCE OF :
COMPLETE BLOOD COUNT : RENAL FUNCTION TEST : LIVER FUNCTION TEST : USG – FIBROID, OVARIAN CYST :
HYSTEROSALPINGOGRAM – FOR TUBAL PATENCY PREVIOUS HISTORY OF SURGERY – YES / NO
FSH - Follicle stimulating hormone LH - Leutinizing harmone
CAMP - Cyclic Adenosine monophosphate LDL - Low density Lipoprotein
HCG - Human chorionic Gonadotrophin FP - Follicular Phase
L.P. - Luteal Phase POD - Pouch of Douglas
PCOS - Polycystic ovarian syndrome CAH - Congenital Adrenal Hyperplasia
MRKA - Meyer – Rokitansky Kuster Hauser syndrome SOL - Space occupying lesion
PrL - Prolactin
NICHD - National Institute for Child Health and Human Development
ESHRE - European Society for Human Reproduction ASRM - American Society for Reproductive Medicine AES - Androgen Excess Society
TGL - Triglycerides
HDL - High Density Lipoprotein BMI - Body mass Index
WHR - Waist Hip Ratio
PAI - Plasminogen Activator Inhibitor OI - Ovulation Induction
OHSS - Ovarian Hyperstimulation Syndrome HSG - Hysterosalpingrography
SERMs - Selective Oestrogen Receptor Modulators GnRH - Gonadotropin Releasing Harmone
HMG - Human Menopausal Gonadotropin OCP - Oral contraceptive pill
L - Letrozole
CC - Clomiphene Citrate
HRT - Hormone Replacement Therapy TVS - Transvaginal Ultrasonography AUB - Abnormal Uterine Bleeding AI - Aromatase Inhibitors
ER - Estrogen Receptor
KEY TO MASTER CHART
Sl.No. - Serial Number
M/s. - Duration of Infertility Ht - Height
Wt - Weight
BMI - Body Mass Index WHR - Waist Hip Ratio Oligo - Oligomenorrhea Amen - Amenorrhea
EMT - Endometrial Thickness Prog - Progesterone
Group 1 - Letrozole